Innovative Strategies for Improved Outcomes in Nephrolithiasis. The main focus of this Program Project Grant is to develop and refine ultrasound-based technologies and treatment protocols to improve the noninvasive removal of stones from the kidney with the goal of improving patient outcomes. In this effort, we will refine new technology that uses ultrasonic propulsion (UP) to push stones and residual stone fragments out of the renal pelvicalyceal system and on to the uretero-pelvic junction for passage down the ureter. The UP system is built upon a commercially available ultrasound (US) platform that we have configured to deliver a suite of unique stone-specific imaging modalities (S-mode) specifically tailored to detect stones (even very small, <1 mm, stone fragments), determine fragment size, detect cavitation indicative of the acoustic shielding that interferes with stone breakage, and localize the cavitation in tissue that signals the on- set of tissue injury. We will use UP and S-mode imaging to improve the efficiency of shock wave lithotripsy (SWL) by dispersing fragments that create shielding and by enabling precise determination of the stone breakage endpoint so that patients are not needlessly over-treated. We will also pursue the development, refinement, and validation of a novel noninvasive method that uses focused, low-frequency pulsed US (burst wave lithotripsy, BWL) to reduce stones to small, clinically insignificant particles with minimal injury to surrounding tissue. Over-treatment by SWL is linked to increased adverse effects and is the basis for FDA limits on SW-dose, limits that often prevent treatment with a dose sufficient to render the patient stone free. We will build upon our discovery of SWL treatment strategies that protect the kidney from injury to devise treatment protocols that dramatically exceed current FDA limits for SW dose, yet are entirely safe. That is, we will demonstrate that single session treatment limits for SWL can be exceeded without causing added injury, thus allowing treatment with enough SWs to fully comminute a large stone burden or eliminate stones otherwise difficult to break. Consistent with our goal of improving treatment outcomes for stone patients, we will conduct a multicenter prospective clinical trial to determine if the removal of 'subclinical' attached stones by ureterorenoscopy (assisted by UP) will forestall stone recurrence, thereby improving long-term outcomes.